Introduction.

Abstract

Haematopoietic cells were used as targets for gene transfer in the first attempts to use gene marking and gene therapy in the clinic. In 1989, Steven Rosenberg marked tumor-infiltrating lymphocytes (TIL) with the neotransferase gene using a retroviral vector in order to show that these reinfused autologous cells targeted the tumour to which they were immunized [1]. Gene-modified lymphocytes were also the first cells used in clinical attempts to cure a genetic disease, i.e. adenosine deaminase deficiency [2]. These early attempts were important, but no patient was cured. Numbers of problems remained, such as insufficient transduction efficacy, poor expression of the genes and unwanted immune responses. This led to a NIH-directed investigation, i.e. the so-called Orkin–Motulsky report [3], which emphasized refocusing on better understanding of target cell and vector biology, new vector design and improvement of gene transfer efficacy. Although this report was important and redirected research funding to more basic research, fortunately it did not have the aim of stopping or prohibiting clinical research on gene therapy. Most of the clinical trials during later years have involved haematopoietic cells or have been directed to treatment of haematopoietic disorders. This symposium will cover both basic research and the dramatic clinical results that have been seen during recent years. Dr Cynthia Dunbar at the National Institutes of Health will describe the development and improvement in gene transfer to haematopoietic cells in non-human primate models, and Stefan Karlsson’s group in Lund will describe and review the studies on lentiviral vectors and the prospects for clinical use. Dr Malcolm Brenner will cover the important developments in gene transfer and gene therapy for haematological malignancies. Brenner’s group could first show, by gene marking, that the bone marrow cells used for autologous transplantation of patients with acute leukaemia could cause relapse [4]. Although the need for purging of malignant cells is still a controversial issue, this study paved the way for further investigations of improving methodology for autologous stem-cell transplantation. Malcolm Brenner will also review other new aspects on gene transfer and gene therapy in haematological malignancies such as the possibility for tumour gene repairing, modulation of the immune response by altering the specificity of effector function of immune cells and how to increase cytotoxic drug resistance of normal cells by gene transfer in order to allow more intensive chemotherapy. The interesting discovery that the antiviral drug ganciclovir will kill cells that have been transduced with the herpes simplex virus thymidine kinase (HSV-tk) gene [5] has led to experimental approaches to treat cancer. A bystander killing effect has been seen in transduced plasma-cell tumours [6]. Sirac Dilber describes the system, as well as new approaches for improvement and prospects for clinical tumour treatment. The HSV-tk-ganciclovir and similar systems have already been used in clinical attempts to modulate graft-versus-host disease. Dr Pierre Thiberghin will describe this approach and the successful abrogation of GVHD by ganciclovir in some patients who had received HSV-tk-transduced donor lymphocytes. Perhaps the most exciting development in clinical gene therapy is the successful treatment of two patients with X-linked severe combined immunodeficiency by a corrected gamma -c gene transduced into autologous CD34 positive stem cells [7]. Recently, Alain Fischer’s group presented 1-year follow-up data on these two patients, who are still cured from the disease. Three further patients have since been treated – two patients have engrafted but are too early to evaluate and engraftment failed in the third. Donald Kohn will review these and other new developments in gene therapy of genetic haematological disorders. Gene therapy is still in its infancy. The research on gene transfer into haematopoietic cells and gene therapy of haematological disorders has been the main contributor to results in gene therapy so far. This is why the Journal of Internal Medicine has chosen to sponsor this symposium on haematopoietic cell gene therapy.